Preface

Evidence obtained from studies over the last decade has demonstrated that some types of hematological malignancies, commonly in acute myeloid leukemia and myelodysplastic syndrome, are associated with germ line mutations either in specific gene mutations or genetic-based syndromes, as described and classified officially by the World Health Organization (WHO) in their book *WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues*, 2016.

The four edited chapters in this book are specific to our aim of increasing the awareness, minimizing the underdiagnosis and even misdiagnosis, preventing the occurrence of secondary malignancies, and providing the appropriate treatment strategies for germ line mutations-associated leukemia. This includes the selection of donors for stem cell transplantation and also care for members of affected families by the application of modern technologies. This is because germ line mutationsassociated leukemia presents different genetic landscapes and more importantly it requires different therapeutical strategies due to the nature and complexity of the disease. We hope this book will help in the understanding of germ line mutationsassociated disease, particularly in leukemogenesis caused by somatic mutations.

Books published on the topic of somatic mutations-associated leukemia are very common, but to our knowledge books published on the topic of germ line mutations-associated leukemia are extremely rare, so far. We all are facing huge challenges but also exciting opportunities in such a special field.

We would like to express our thanks for the contributions from all the experienced authors as follows:

Epigenetics is the concept of genetic functional modification and plays a very important biological role in the control of gene expression without changing the DNA sequence. Studies have found that epigenetics is associated with cancer. Dr. Duohui Jing, Dr. Richard B Lock, Dr. Julia Cathryn Hlavka-Zhang, and Dr. Bingzhi He have contributed their chapter "Epigenetic Landscape in Leukemia and Its Impact on Antileukemia Therapeutics" in which they discuss their novel findings obtained from first-hand studies on the mechanism of therapeutical resistance from specific epigenetic modification.

As mentioned above, WHO has specifically described and classified the myeloid neoplasmas with germ line predisposition and pre-existing platelet disorders. Dr. Jakub Trizuljak and Dr. Michael Doubek have contributed their chapter "Familial Leukemia Associated with Thrombocytopenia" by discussing the association of familial/inherited platelet disorders with germ line mutations-associated leukemia.

Dr. Arturo Solis Herrera has contributed his chapter "Perturbations in Generation and Flow of Energy in the Eukaryotic Cell Explain the Chromosomal Instability Syndrome" from different fields and directions to discuss the association of the pathological mechanism of leukemia.

We also would like to thank the Author Service Manager, Ms. Sandra Maljavac, for her skillful organization and great efforts.

> **Zhan He Wu** Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Affiliated to the University of Sydney, Australia

> > **1**

Section 1

Introduction

Section 1 Introduction

**3**

**Chapter 1**

Strategies

*Zhan He Wu*

**1. Introduction**

the cells themselves".

Introductory Chapter: Germline

Leukaemia - Different Genetic

Dr. Barbara McClintock, the 1983 Nobel Prize winner in physiology or medicine, described that "the most remarkable kinds of mutations are not (usually) produced by such extrinsic factors as radiation and chemicals, but by factors that are intrinsic to

Evidences obtained from studies proved that genomic mutations are the direct root causes of increased susceptibility to almost all disorders/diseases in the manner of either somatic or germline mutations. Diseases associated with somatic mutations have been well studied; in contrast, studies on diseases associated with

The estimation by 2015 showed that there were about 17.5 million cancer cases and 8.7 million deaths worldwide per annum [1]. Cancer is a genetic disease caused by mutations from environmental and genetic factors and their interactions. Genetic factors include somatic (acquired) and germline: the difference between germline and somatic mutations is that the germline mutation occurring in reproductive cells (sperm, egg) inherits to the offspring, whereas somatic mutation

In the recent years, more and more attention has been paid to the studies on cancers associated with germline mutations, and more and more discoveries have been achieved by increasing the recognition of such disease. TP53 was the typical and most commonly germline-mutated gene associated with Li-Fraumeni syndrome (colorectal cancer). Studies from Zhang group showed that the rate of germline mutation in cancer-predisposition genes was 8.5%. They estimated that in the hereditary breast/ovarian cancer (HBOC) from BRCA1 and BRAC2 mutations, women with BRCA1 mutations have a 47–66% chance of developing breast cancer and a 35–46% chance of developing ovarian cancer by the age of 70 years [2].

Leukaemia is a type of haematological malignancy (liquid cancer) occurring in haematopoietic tissue caused by environmental and genetic factors, such as other types of cancers, typically presented with fever, bleeding, infection, bone pain and anaemia. The presentation can vary, however, depending on the many different factors of individuals. Among all leukaemia types of the myeloid malignancies, acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS) and chronic myeloid

germline mutations have been just started, particularly in malignancies.

occurring in body cells is not inherent to the offspring.

leukaemia (CML) are the common types.

Mutations Associated with

Landscape and Therapeutic

#### **Chapter 1**

## Introductory Chapter: Germline Mutations Associated with Leukaemia - Different Genetic Landscape and Therapeutic Strategies

*Zhan He Wu*

#### **1. Introduction**

Dr. Barbara McClintock, the 1983 Nobel Prize winner in physiology or medicine, described that "the most remarkable kinds of mutations are not (usually) produced by such extrinsic factors as radiation and chemicals, but by factors that are intrinsic to the cells themselves".

Evidences obtained from studies proved that genomic mutations are the direct root causes of increased susceptibility to almost all disorders/diseases in the manner of either somatic or germline mutations. Diseases associated with somatic mutations have been well studied; in contrast, studies on diseases associated with germline mutations have been just started, particularly in malignancies.

The estimation by 2015 showed that there were about 17.5 million cancer cases and 8.7 million deaths worldwide per annum [1]. Cancer is a genetic disease caused by mutations from environmental and genetic factors and their interactions. Genetic factors include somatic (acquired) and germline: the difference between germline and somatic mutations is that the germline mutation occurring in reproductive cells (sperm, egg) inherits to the offspring, whereas somatic mutation occurring in body cells is not inherent to the offspring.

In the recent years, more and more attention has been paid to the studies on cancers associated with germline mutations, and more and more discoveries have been achieved by increasing the recognition of such disease. TP53 was the typical and most commonly germline-mutated gene associated with Li-Fraumeni syndrome (colorectal cancer). Studies from Zhang group showed that the rate of germline mutation in cancer-predisposition genes was 8.5%. They estimated that in the hereditary breast/ovarian cancer (HBOC) from BRCA1 and BRAC2 mutations, women with BRCA1 mutations have a 47–66% chance of developing breast cancer and a 35–46% chance of developing ovarian cancer by the age of 70 years [2].

Leukaemia is a type of haematological malignancy (liquid cancer) occurring in haematopoietic tissue caused by environmental and genetic factors, such as other types of cancers, typically presented with fever, bleeding, infection, bone pain and anaemia. The presentation can vary, however, depending on the many different factors of individuals. Among all leukaemia types of the myeloid malignancies, acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS) and chronic myeloid leukaemia (CML) are the common types.

In a similar scenario with germline mutations associated with solid cancers, about 5–10% of some particular germline mutations will develop to haematological malignancies including MDS, MDS/myeloproliferative neoplasms (MPN) and AML. Germline predisposition of myeloid malignancies is estimated at about 5–10% in the genetic manner, either from functional haplo-insufficiency due to loss of an allele or gain of oncogenic function, but the loss of an allele is more common than gain of oncogenic function in such a type of leukaemia [3].

Studies showed that myeloid neoplasms associated with predisposing of germline mutations are found to be more common than was thought. But it is still underinvestigated, under-diagnosed and under-reported due to the low case numbers and nature of disease complexity.

#### **2. Understanding of the WHO's germline mutations associated with neoplasms from gene mutations and syndromes**

To increase the recognition for germline predisposition, the major changes were made in the 2016 version of the book *WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues* for the myeloid neoplasms, with the addition of germline predisposition of the myeloid neoplasms under the following categories [4, 5]:

**The first category** is myeloid neoplasms with germline predisposition without a pre-existing disorder or organ dysfunction with CEBPA and DDX41 mutations.

CCAAT enhancer-binding protein alpha (CEBPA) is involved in the function of myeloid differentiation by encoding a granulocyte differentiation factor located on chromosome 19q13.1. This germline mutation associated with AML is due to the inheritance of a single copy of mutated CEBPA, and studies suggested such mutation has a favourable prognosis than somatic mutation AML [6, 7].

DEAD-Box Helicase (DDX41) is located on chromosome 5q35.3, and studies found that in about 1.5% of myeloid neoplasms, half of these patients had germline mutations, typically in MDS and AML combined with additional del(5q) presented with erythroid dysplasia, leading to erythroid leukaemia with poor prognosis. CML, CMML and lymphomas have been also reported [8, 9].

**The second category** is myeloid neoplasms with germline predisposition and pre-existing platelet disorders with RUNX1, ANKRD26 and ETV6 mutations.

Runt-related transcription factor 1 (RUNX1, located on chromosome 21q.12) is playing a physiological role in haematopoiesis. RUNX1 mutations cause familial platelet disorder and develop to MDS/AML in 11–100% risk, median 44% [10, 11].

Ankyrin repeat domain-containing protein 26 (ANKRD26, located on chromosome 10p12.1) mutation is characterised by thrombocytopenia from the abnormal megakaryopoiesis and increases risk to MDS and AML in about 30 fold [12, 13].

ETS variant gene 6 (ETV6, located on chromosome 12p13.2) is functional as a haematopoietic regulator in normal physiological condition. ETV6 mutations were found to be associated with several types of haematological malignancies including MDS, AML, B-cell leukaemia and multiple myeloma (MM) as have been identified [14–17].

**The third category** is the myeloid neoplasms with germline predisposition and other organ dysfunctions with GATA2 mutations and several types of geneticbased syndromes including myeloid neoplasms associated with telomere biology disorders, juvenile myelomonocytic leukaemia associated with neurofibromatosis, Noonan syndrome or Noonan syndrome-like disorders and myeloid neoplasms associated with Down syndrome.

GATA-binding protein 2 (GATA2, located on chromosome 3q21.3) mutations were found to be associated with some syndromes, including MonoMac syndrome, dendritic cell, monocyte, B and NK cell deficiency, familial MDS and Emberger

**5**

cancer and ageing.

*Introductory Chapter: Germline Mutations Associated with Leukaemia - Different Genetic…*

syndrome and some types of disorders such as congenital neutropenia and aplastic anaemia. The risk of developing MDS/AML from GATA2 germline mutations is

**3. Germline mutations associated with haematological malignancies in** 

Most of the findings of germline mutations associated with leukaemia were from myeloid neoplasms. Recent studies found that lymphoid malignancies in acute lymphoblastic leukaemia (ALL) and chronic lymphocytic leukaemia (CLL) are associated with germline mutations. Speedy et al. demonstrated the existence of germline mutations associated with familial CLL by using whole-exome sequencing of 66 CLL families and identified 4 families where loss-of-function mutations in protection of telomeres 1 (POT1) co-segregated with CLL [22]. Qian group studied the loss-of-function germline TP53 variants, and their results suggested that such mutations lead to predispose children to ALL and with adverse treatment outcomes with ALL therapy and increase the risk of second malignant neoplasms [23]. Chang et al. have identified germline mutations from congenital ALL by using the exome

Studies showed that some more genetic-based cancer-prone syndromes with specific germline predisposition syndromes and multiple-cancer hereditary predisposition syndromes are all at an increased risk for haematologic malignancies, commonly in AML, including chromosomal instability syndromes (CIS) such as Nijmegen breakage syndrome, Ataxia telangiectasia, Ataxia telangiectasia-like disorder and Bloom syndrome and including inherited bone marrow failure syndromes (IBMFS) such as dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anaemia, congenital amegakaryocytic thrombocytopenia, severe congenital neutropenia and thrombocytopenia-absent radii [25].

The most representative example is the Fanconi anaemia (FA) with germline mutations and predisposition to leukaemia. It overlaps in both CIS and IBMFS in its phenotypes. Historically, it was first recognised as a cause of juvenile leukaemia in 1967 [26]. FA is a hereditary disorder with defects in DNA repair and is characterised with multiple gene mutations, multiple types of genetic abnormalities, multiple organ involvements and multiple types of cancer risks [27, 28]. So far, 22 genes responsible for FA have been identified, 4 of them are genes found in breast cancer and some genes were found to be associated with other types of cancers as well. Patients with FA have very high susceptibility to both haematologic and nonhaematologic malignancies. The risk of developing AML and MDS is increased to 785 fold, and the median age of patients developing to AML is 14 years. AML occurs at about 9% and MDS is about 7% of all patients with FA, respectively [29]. Cells from FA patient associated with leukaemia showed high sensitive reaction to

FA was the first successful remarkable milestone in cord blood stem cell transplantation in 1988. The studies on FA offered insights into the pathogenesis of many types of human diseases, particularly in non-genetic bone marrow failure, ageing and cancer. So the study on FA is named as a paradigm for the understanding of

In the last couple of years, studies, by using the modern genetic technologies particularly by the next-generation sequencing (NGS) approach to study known and new germline mutations in familial acute myeloid leukaemia and myelodysplastic syndromes, found more leukaemia predisposition genes associated with germ line in variants in cancer-predisposition genes, mainly as ASXL1, BCOR, NRAS,

chemotherapies than non-FA patient with leukaemia.

*DOI: http://dx.doi.org/10.5772/intechopen.86154*

**myeloid and lymphoid leukaemias**

increased by 70% [18, 19, 20, 21].

sequencing technology [24].

*Introductory Chapter: Germline Mutations Associated with Leukaemia - Different Genetic… DOI: http://dx.doi.org/10.5772/intechopen.86154*

syndrome and some types of disorders such as congenital neutropenia and aplastic anaemia. The risk of developing MDS/AML from GATA2 germline mutations is increased by 70% [18, 19, 20, 21].

#### **3. Germline mutations associated with haematological malignancies in myeloid and lymphoid leukaemias**

Most of the findings of germline mutations associated with leukaemia were from myeloid neoplasms. Recent studies found that lymphoid malignancies in acute lymphoblastic leukaemia (ALL) and chronic lymphocytic leukaemia (CLL) are associated with germline mutations. Speedy et al. demonstrated the existence of germline mutations associated with familial CLL by using whole-exome sequencing of 66 CLL families and identified 4 families where loss-of-function mutations in protection of telomeres 1 (POT1) co-segregated with CLL [22]. Qian group studied the loss-of-function germline TP53 variants, and their results suggested that such mutations lead to predispose children to ALL and with adverse treatment outcomes with ALL therapy and increase the risk of second malignant neoplasms [23]. Chang et al. have identified germline mutations from congenital ALL by using the exome sequencing technology [24].

Studies showed that some more genetic-based cancer-prone syndromes with specific germline predisposition syndromes and multiple-cancer hereditary predisposition syndromes are all at an increased risk for haematologic malignancies, commonly in AML, including chromosomal instability syndromes (CIS) such as Nijmegen breakage syndrome, Ataxia telangiectasia, Ataxia telangiectasia-like disorder and Bloom syndrome and including inherited bone marrow failure syndromes (IBMFS) such as dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anaemia, congenital amegakaryocytic thrombocytopenia, severe congenital neutropenia and thrombocytopenia-absent radii [25].

The most representative example is the Fanconi anaemia (FA) with germline mutations and predisposition to leukaemia. It overlaps in both CIS and IBMFS in its phenotypes. Historically, it was first recognised as a cause of juvenile leukaemia in 1967 [26]. FA is a hereditary disorder with defects in DNA repair and is characterised with multiple gene mutations, multiple types of genetic abnormalities, multiple organ involvements and multiple types of cancer risks [27, 28]. So far, 22 genes responsible for FA have been identified, 4 of them are genes found in breast cancer and some genes were found to be associated with other types of cancers as well.

Patients with FA have very high susceptibility to both haematologic and nonhaematologic malignancies. The risk of developing AML and MDS is increased to 785 fold, and the median age of patients developing to AML is 14 years. AML occurs at about 9% and MDS is about 7% of all patients with FA, respectively [29]. Cells from FA patient associated with leukaemia showed high sensitive reaction to chemotherapies than non-FA patient with leukaemia.

FA was the first successful remarkable milestone in cord blood stem cell transplantation in 1988. The studies on FA offered insights into the pathogenesis of many types of human diseases, particularly in non-genetic bone marrow failure, ageing and cancer. So the study on FA is named as a paradigm for the understanding of cancer and ageing.

In the last couple of years, studies, by using the modern genetic technologies particularly by the next-generation sequencing (NGS) approach to study known and new germline mutations in familial acute myeloid leukaemia and myelodysplastic syndromes, found more leukaemia predisposition genes associated with germ line in variants in cancer-predisposition genes, mainly as ASXL1, BCOR, NRAS,

*Germ Line Mutations Associated Leukemia*

nature of disease complexity.

In a similar scenario with germline mutations associated with solid cancers, about 5–10% of some particular germline mutations will develop to haematological malignancies including MDS, MDS/myeloproliferative neoplasms (MPN) and AML. Germline predisposition of myeloid malignancies is estimated at about 5–10% in the genetic manner, either from functional haplo-insufficiency due to loss of an allele or gain of oncogenic function, but the loss of an allele is more common

Studies showed that myeloid neoplasms associated with predisposing of germline mutations are found to be more common than was thought. But it is still underinvestigated, under-diagnosed and under-reported due to the low case numbers and

**2. Understanding of the WHO's germline mutations associated with** 

pre-existing disorder or organ dysfunction with CEBPA and DDX41 mutations. CCAAT enhancer-binding protein alpha (CEBPA) is involved in the function of myeloid differentiation by encoding a granulocyte differentiation factor located on chromosome 19q13.1. This germline mutation associated with AML is due to the inheritance of a single copy of mutated CEBPA, and studies suggested such muta-

DEAD-Box Helicase (DDX41) is located on chromosome 5q35.3, and studies found that in about 1.5% of myeloid neoplasms, half of these patients had germline mutations, typically in MDS and AML combined with additional del(5q) presented with erythroid dysplasia, leading to erythroid leukaemia with poor prognosis.

**The second category** is myeloid neoplasms with germline predisposition and pre-existing platelet disorders with RUNX1, ANKRD26 and ETV6 mutations. Runt-related transcription factor 1 (RUNX1, located on chromosome 21q.12) is playing a physiological role in haematopoiesis. RUNX1 mutations cause familial platelet disorder and develop to MDS/AML in 11–100% risk, median 44% [10, 11]. Ankyrin repeat domain-containing protein 26 (ANKRD26, located on chromosome 10p12.1) mutation is characterised by thrombocytopenia from the abnormal megakaryopoiesis and increases risk to MDS and AML in about 30 fold [12, 13]. ETS variant gene 6 (ETV6, located on chromosome 12p13.2) is functional as a haematopoietic regulator in normal physiological condition. ETV6 mutations were found to be associated with several types of haematological malignancies including MDS, AML, B-cell leukaemia and multiple myeloma (MM) as have been identified [14–17]. **The third category** is the myeloid neoplasms with germline predisposition and other organ dysfunctions with GATA2 mutations and several types of geneticbased syndromes including myeloid neoplasms associated with telomere biology disorders, juvenile myelomonocytic leukaemia associated with neurofibromatosis, Noonan syndrome or Noonan syndrome-like disorders and myeloid neoplasms

GATA-binding protein 2 (GATA2, located on chromosome 3q21.3) mutations were found to be associated with some syndromes, including MonoMac syndrome, dendritic cell, monocyte, B and NK cell deficiency, familial MDS and Emberger

To increase the recognition for germline predisposition, the major changes were made in the 2016 version of the book *WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues* for the myeloid neoplasms, with the addition of germline predis-

**The first category** is myeloid neoplasms with germline predisposition without a

than gain of oncogenic function in such a type of leukaemia [3].

**neoplasms from gene mutations and syndromes**

position of the myeloid neoplasms under the following categories [4, 5]:

tion has a favourable prognosis than somatic mutation AML [6, 7].

CML, CMML and lymphomas have been also reported [8, 9].

**4**

associated with Down syndrome.

TP53, CEBPA, FLT3, EZH2, IDH1, IDH2, NPM1, DNMT3A, TET2, CBL, KRAS, SF3B1, SRSF2, U2AF1, ZRSR2, TERT, TERC and SRP72 [30–32]. Studies from Seiter group provided the direct evidence from ASXL1 germline mutation associated with leukaemia studied on father and son [33]. Buijs et al. defined CBFA2 singlenucleotide mutation in a familial leukaemia [34].

Recommendations and guides are available by the applications of the nextgeneration sequencing approaches (NGS) [35, 36]. Churpek et al. proposed recommendations on the screening, identification, genetic counselling and managements on inherited susceptibility to MDS and acute leukaemia [37].

#### **4. Conclusion**

To increase the awareness and recognition for germline mutations associated with leukaemia is extremely important and imperative in the clinical practice by performing the specific tests. The significances are (1) to diagnose such type of patients earlier even if before the occurrence of such type of leukaemia, (2) to prevent the occurrence of secondary cancers, (3) to care other members of the family, (4) to design a specific therapeutical strategy, personalised medicine and long-term follow-up and (5) to guide the selection of donors for patient bone marrow stem cell transplantation.

To study germline mutations and syndromes associated with leukaemia has provided exciting and significant opportunities with such new discoveries. The studies on germline mutations associated with leukaemia will not only be useful in its clinical diagnosis, classification, stratification and specific treatment strategies, but it will also provide an insight to understand human diseases, such as tumorigenesis, particularly in somatic mutations associated with leukemogenesis. It is certainly that more and more such disorders will be identified in the future.

The huge challenges are to identify germline mutation associated with leukaemia due to the lack of awareness and knowledge about these disorders, lack of at least easy and practical available testing methods and sufficient familial history of individuals and lack of specimen source to represent genome for these individuals. The complex and mysterious genetic variation is another challenging issue just as the English novelist, George Orwell, described that "all cancer is genetic, but some cancers are more genetic than others which it hinted the mechanism and genetic variations of cancers".

#### **Author details**

Zhan He Wu Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's Hospital at Westmead, NSW, Australia

\*Address all correspondence to: zhan.wu@health.nsw.gov.au.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**7**

*Introductory Chapter: Germline Mutations Associated with Leukaemia - Different Genetic…*

[9] Bannon SA, DiNardo CD. Hereditary predispositions to myelodysplastic syndrome. International Journal of Molecular Sciences. 2016;**17**:2-11

[10] Owen CJ, Toze CL, Anna Koochin A, et al. Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood.

[11] Bellissimo DC, Speck NA. RUNX1

[13] Noris P, Favier R, Alessi MC, et al. ANKRD26-related thrombocytopenia and myeloid malignancies. Blood.

[14] Zhang MY, Churpek JE, Keel SB, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nature Genetics. 2015;**47**(2):180-185

[15] Noetzli L, Lo RW, Lee-Sherick AB, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nature Genetics. 2015;**47**(5):535-538

[16] Topka S, Vijai J, Walsh MF, et al. Germline ETV6 mutations confer susceptibility to acute lymphoblastic leukemia and thrombocytopenia. PLoS

[17] Moriyama T, Metzger ML, Wu G, et al. Germline genetic variation in

Genetics. 2015;**11**(6):1-14

2008;(12):4639-4645

2017;**5**(111):1-11

2011;**117**:6673-6680

2013;**122**:1987-1989

mutations in inherited and sporadic leukemia. Frontiers in Cell and Developmental Biology.

[12] Noris P, Perrotta S, Seri M, et al. Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: Analysis of 78 patients from 21 families. Blood.

*DOI: http://dx.doi.org/10.5772/intechopen.86154*

[1] Fitzmaurice C. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015, a systematic analysis for the global burden of disease study. JAMA

[2] Ngeow J, Eng C. Precision medicine in heritable cancer: When somatic tumour testing and germline mutations meet. NPJ Genomic Medicine. 2016;**1**:1-3

[3] Zhang JH, Walsh MF, Wu G, et al. Germline mutations in predisposition

[4] Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised. 4th ed. Vol. 22017. International Agency for Research on Cancer. Lyon, France; pp. 121-128

[5] Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.

[6] Godley LA. Inherited predisposition to acute myeloid leukemia. Seminars in Hematology. 2014;**51**(4):306-321

[7] Pabst T, Eyholzer M, Fos J, et al. Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis. British Journal of

[8] West AH, Godley LA, Churpek JE. Familial myelodysplastic syndrome/ acute leukemia syndromes: A review and utility for translational investigations. Annals of the New York Academy of Sciences.

Cancer. 2009;**100**:1343-1346

2014;**1310**:111-118

Blood. 2016;**127**(20):2391-2405

genes in pediatric cancer. The New England Journal of Medicine.

2015;**373**:2336-2346

Oncology. 2017;**3**(4):524-548

**References**

*Introductory Chapter: Germline Mutations Associated with Leukaemia - Different Genetic… DOI: http://dx.doi.org/10.5772/intechopen.86154*

#### **References**

*Germ Line Mutations Associated Leukemia*

**4. Conclusion**

variations of cancers".

**Author details**

Zhan He Wu

nucleotide mutation in a familial leukaemia [34].

on inherited susceptibility to MDS and acute leukaemia [37].

that more and more such disorders will be identified in the future.

TP53, CEBPA, FLT3, EZH2, IDH1, IDH2, NPM1, DNMT3A, TET2, CBL, KRAS, SF3B1, SRSF2, U2AF1, ZRSR2, TERT, TERC and SRP72 [30–32]. Studies from Seiter group provided the direct evidence from ASXL1 germline mutation associated with leukaemia studied on father and son [33]. Buijs et al. defined CBFA2 single-

Recommendations and guides are available by the applications of the nextgeneration sequencing approaches (NGS) [35, 36]. Churpek et al. proposed recommendations on the screening, identification, genetic counselling and managements

To increase the awareness and recognition for germline mutations associated with leukaemia is extremely important and imperative in the clinical practice by performing the specific tests. The significances are (1) to diagnose such type of patients earlier even if before the occurrence of such type of leukaemia, (2) to prevent the occurrence of secondary cancers, (3) to care other members of the family, (4) to design a specific therapeutical strategy, personalised medicine and long-term follow-up and (5) to guide the selection of donors for patient bone marrow stem cell transplantation.

To study germline mutations and syndromes associated with leukaemia has provided exciting and significant opportunities with such new discoveries. The studies on germline mutations associated with leukaemia will not only be useful in its clinical diagnosis, classification, stratification and specific treatment strategies, but it will also provide an insight to understand human diseases, such as tumorigenesis, particularly in somatic mutations associated with leukemogenesis. It is certainly

The huge challenges are to identify germline mutation associated with leukaemia due to the lack of awareness and knowledge about these disorders, lack of at least easy and practical available testing methods and sufficient familial history of individuals and lack of specimen source to represent genome for these individuals. The complex and mysterious genetic variation is another challenging issue just as the English novelist, George Orwell, described that "all cancer is genetic, but some cancers are more genetic than others which it hinted the mechanism and genetic

**6**

provided the original work is properly cited.

Hospital at Westmead, NSW, Australia

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's

\*Address all correspondence to: zhan.wu@health.nsw.gov.au.

[1] Fitzmaurice C. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015, a systematic analysis for the global burden of disease study. JAMA Oncology. 2017;**3**(4):524-548

[2] Ngeow J, Eng C. Precision medicine in heritable cancer: When somatic tumour testing and germline mutations meet. NPJ Genomic Medicine. 2016;**1**:1-3

[3] Zhang JH, Walsh MF, Wu G, et al. Germline mutations in predisposition genes in pediatric cancer. The New England Journal of Medicine. 2015;**373**:2336-2346

[4] Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised. 4th ed. Vol. 22017. International Agency for Research on Cancer. Lyon, France; pp. 121-128

[5] Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;**127**(20):2391-2405

[6] Godley LA. Inherited predisposition to acute myeloid leukemia. Seminars in Hematology. 2014;**51**(4):306-321

[7] Pabst T, Eyholzer M, Fos J, et al. Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis. British Journal of Cancer. 2009;**100**:1343-1346

[8] West AH, Godley LA, Churpek JE. Familial myelodysplastic syndrome/ acute leukemia syndromes: A review and utility for translational investigations. Annals of the New York Academy of Sciences. 2014;**1310**:111-118

[9] Bannon SA, DiNardo CD. Hereditary predispositions to myelodysplastic syndrome. International Journal of Molecular Sciences. 2016;**17**:2-11

[10] Owen CJ, Toze CL, Anna Koochin A, et al. Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood. 2008;(12):4639-4645

[11] Bellissimo DC, Speck NA. RUNX1 mutations in inherited and sporadic leukemia. Frontiers in Cell and Developmental Biology. 2017;**5**(111):1-11

[12] Noris P, Perrotta S, Seri M, et al. Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: Analysis of 78 patients from 21 families. Blood. 2011;**117**:6673-6680

[13] Noris P, Favier R, Alessi MC, et al. ANKRD26-related thrombocytopenia and myeloid malignancies. Blood. 2013;**122**:1987-1989

[14] Zhang MY, Churpek JE, Keel SB, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nature Genetics. 2015;**47**(2):180-185

[15] Noetzli L, Lo RW, Lee-Sherick AB, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nature Genetics. 2015;**47**(5):535-538

[16] Topka S, Vijai J, Walsh MF, et al. Germline ETV6 mutations confer susceptibility to acute lymphoblastic leukemia and thrombocytopenia. PLoS Genetics. 2015;**11**(6):1-14

[17] Moriyama T, Metzger ML, Wu G, et al. Germline genetic variation in

ETV6 and risk of childhood acute lymphoblastic leukaemia: A systematic genetic study. The Lancet Oncology. 2015;**16**(16):1659-1666

[18] Hahn CN, Chong CE, Carmichael CL, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nature Genetics. 2011;**43**(10):1012-1017

[19] Ostergaard P, Simpson MA Connell FC, et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nature Genetics. 2011;**43**:929-931

[20] Micol JB, Abdel-Wahab O. ASXL1 mutations in patients with germline GATA2 mutations. Haematologica. 2014;**99**(2):201-203

[21] Mateos MK, Barbaric D, Sally-Anne Byatt SA, et al. Down syndrome and leukemia: Insights into leukemogenesis and translational targets. Translational Pediatrics. 2015;**4**(2):76-92

[22] Speedy HE, Kinnersley B, Chubb D, et al. Germline mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia. Blood. 2016;**128**(19):2319-2326

[23] Qian M, Cao X, Devidas M, et al. TP53 germline variations influence the predisposition and prognosis of B-cell acute lymphoblastic leukemia in children. Journal of Clinical Oncology. 2018;**36**:591-599

[24] Chang CY, Basso G, Sakamoto KM, et al. Identification of somatic and germline mutations using whole exome sequencing of congenital acute lymphoblastic leukemia. BMC Cancer. 2013;**13**:55

[25] Wu ZH. Inherited bone marrow failure and chromosome instability syndromes and their cancer predisposition. In: Hassan, editor.

Contemporary Pediatric Hematology and Oncology. UK: IntechOpen; 2019. pp. 1-20

[26] Fanconi G. Familiäre infantile perniziosaartige Anämie (pernizioses Blutbild und Konstitution). Jahrb Kinderh. 1927;**117**:257-280

[27] Wu ZH. The concept and practice of Fanconi anemia: From the clinical bedside to the laboratory bench. Translational Pediatrics. 2013;**2**(3):112-119

[28] Rosenberg P, Greene MH, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood. 2003;**101**:822-826

[29] Alter BP. Cancer in Fanconi anemia 1927-2001. Cancer. 2003;**97**:425-440

[30] Kirwan M, Walne AJ, Plagnol V, et al. Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia. The American Journal of Human Genetics. 2012;**90**:888-892

[31] Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults. ELN recommendations from an international expert panel. Blood. 2017;**129**(4):424-447

[32] Rocquain J, Carbuccia N, Trouplin V, et al. Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias. BMC Cancer. 2010;**10**:401. DOI: 10.1186/1471-2407-10-401

[33] Seiter K, Htun K, Baskind P, et al. Acute myeloid leukemia in a father and son with a germline mutation of ASXL1. Biomarker Research. 2018;**6**:7. DOI: 10.1186/s40364-018-0121-3

[34] Buijs A, Poddighe P, van Wijk R, et al. A novel CBFA2 single-nucleotide

**9**

*Introductory Chapter: Germline Mutations Associated with Leukaemia - Different Genetic…*

*DOI: http://dx.doi.org/10.5772/intechopen.86154*

mutation in familial platelet disorder with propensity to develop myeloid malignancies. Blood. 2001;**98**:2856-2858

[35] Hussaini MO, Mirza A-S, Komrokji R et al. Genetic Landscape of Acute Myeloid Leukemia Interrogated by Next-generation Sequencing: A Large Cancer Center Experience. Cancer Genomics & Proteomics.

2018;**15**:121-126

2016;**128**:1800-1813

[36] The University of Chicago Hematopoietic Malignancies Cancer Risk Team. How I diagnose and manage individuals at risk for inherited myeloid malignancies. Blood.

[37] Churpek JE, Lorenz R, Nedumgottil

S, et al. Proposal for the clinical detection and management of patients and their family members with familial myelodysplastic syndrome/acute leukemia predisposition syndromes. Leukemia & Lymphoma. 2013;**54**:28-35

*Introductory Chapter: Germline Mutations Associated with Leukaemia - Different Genetic… DOI: http://dx.doi.org/10.5772/intechopen.86154*

mutation in familial platelet disorder with propensity to develop myeloid malignancies. Blood. 2001;**98**:2856-2858

*Germ Line Mutations Associated Leukemia*

ETV6 and risk of childhood acute lymphoblastic leukaemia: A systematic genetic study. The Lancet Oncology.

[18] Hahn CN, Chong CE, Carmichael CL, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nature Genetics. 2011;**43**(10):1012-1017

Contemporary Pediatric Hematology and Oncology. UK: IntechOpen; 2019.

[26] Fanconi G. Familiäre infantile perniziosaartige Anämie (pernizioses Blutbild und Konstitution). Jahrb

Kinderh. 1927;**117**:257-280

2013;**2**(3):112-119

2003;**101**:822-826

[27] Wu ZH. The concept and practice of Fanconi anemia: From the clinical bedside to the laboratory bench. Translational Pediatrics.

Cancer incidence in persons with Fanconi anemia. Blood.

[28] Rosenberg P, Greene MH, Alter BP.

[29] Alter BP. Cancer in Fanconi anemia 1927-2001. Cancer. 2003;**97**:425-440

[30] Kirwan M, Walne AJ, Plagnol V, et al. Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia. The American Journal of Human Genetics. 2012;**90**:888-892

[31] Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults. ELN recommendations from an international expert panel.

[32] Rocquain J, Carbuccia N, Trouplin V, et al. Combined mutations of ASXL1, CBL,

Blood. 2017;**129**(4):424-447

FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias. BMC Cancer. 2010;**10**:401. DOI: 10.1186/1471-2407-10-401

[33] Seiter K, Htun K, Baskind P, et al. Acute myeloid leukemia in a father and son with a germline mutation of ASXL1. Biomarker Research. 2018;**6**:7. DOI:

[34] Buijs A, Poddighe P, van Wijk R, et al. A novel CBFA2 single-nucleotide

10.1186/s40364-018-0121-3

pp. 1-20

[19] Ostergaard P, Simpson MA Connell FC, et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nature

[20] Micol JB, Abdel-Wahab O. ASXL1 mutations in patients with germline GATA2 mutations. Haematologica.

[21] Mateos MK, Barbaric D, Sally-Anne Byatt SA, et al. Down syndrome and leukemia: Insights into leukemogenesis and translational targets. Translational

[22] Speedy HE, Kinnersley B, Chubb D, et al. Germline mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.

2015;**16**(16):1659-1666

Genetics. 2011;**43**:929-931

Pediatrics. 2015;**4**(2):76-92

Blood. 2016;**128**(19):2319-2326

2018;**36**:591-599

2013;**13**:55

[23] Qian M, Cao X, Devidas M, et al. TP53 germline variations influence the predisposition and prognosis of B-cell acute lymphoblastic leukemia in children. Journal of Clinical Oncology.

[24] Chang CY, Basso G, Sakamoto KM, et al. Identification of somatic and germline mutations using whole exome sequencing of congenital acute lymphoblastic leukemia. BMC Cancer.

[25] Wu ZH. Inherited bone marrow failure and chromosome instability syndromes and their cancer predisposition. In: Hassan, editor.

2014;**99**(2):201-203

**8**

[35] Hussaini MO, Mirza A-S, Komrokji R et al. Genetic Landscape of Acute Myeloid Leukemia Interrogated by Next-generation Sequencing: A Large Cancer Center Experience. Cancer Genomics & Proteomics. 2018;**15**:121-126

[36] The University of Chicago Hematopoietic Malignancies Cancer Risk Team. How I diagnose and manage individuals at risk for inherited myeloid malignancies. Blood. 2016;**128**:1800-1813

[37] Churpek JE, Lorenz R, Nedumgottil S, et al. Proposal for the clinical detection and management of patients and their family members with familial myelodysplastic syndrome/acute leukemia predisposition syndromes. Leukemia & Lymphoma. 2013;**54**:28-35

**11**

Section 2

Epigenetic Mechanisms

Associated Leukemia

### Section 2
